Proteolytic activity that destroys lung elastic fibers is considered pivotal in the pathogenesis of pulmonary emphysema, a condition found primarily among smokers with chronic obstructive lung disease (COPD). Neutrophils and alveolar macrophages have been examined closely as possible sources for the elastase activity that causes emphysema. While some evidence suggests an important role for neutrophils, several observations point to alveolar macrophages as critical in the pathogenesis of emphysema in smokers: smokers' lungs have greatly increased (10 to 20 fold) numbers of macrophages, macrophages accumulate in smokers' lungs at precisely the sites of early emphysema, and macrophages are known to release a variety of proteinases that can attack components of the extracellular matrix. Furthermore, we have demonstrated that human alveolar macrophages cultured in contact with elastin have significant capacity to degrade this substrate via a mechanism which is near completely metalloproteinase-dependent. Despite these suggestive features, however, it has proven difficult to implicate human macrophages directly in the pathogenesis of emphysema because there has been limited evidence for a human macrophage enzyme with the capacity to degrade elastin. Recently, we discovered that one of the major proteinases released by human alveolar macrophages, a 92-kDa metalloproteinase, has pronounced elastolytic activity. This finding represents the first definitive demonstration of a neutral proteinase secreted by human macrophages that degrades elastin. To extend these initial observations we propose to examine in detail the elastolytic properties of the 92-kDa metalloproteinase, determine the role of this enzyme in the capacity of human alveolar macrophages to degrade elastin, look for evidence of excessive 92-kDa enzyme in human lung tissue affected with emphysema, and establish whether this human enzyme can produce pulmonary emphysema in experimental animals. These studies will use: (1) enzymologic techniques to define the binding affinity of the 92-kDa enzyme for elastin, its catalytic parameters, and sites of substrate cleavage; (2) specific antiserum to the 92-kDa enzyme and the administration of antisense oligonucleotides to block endogenous 92-kDa enzyme and determine its role in macrophage-mediated elastolysis; (3) in situ hybridization to localize expression of 92-kDa mRNA in emphysematous human lung tissues, and; (4) histopathology to determine the effects of recombinant 92-kDa metalloproteinase on the lungs of experimental animals. These studies will contribute new ideas to our understanding of the pathogenesis of emphysema and will lead to new strategies for the prevention and control of emphysema and COPD.